Process for the Manufacture of Epoxybutanol Intermediates

ABSTRACT

Disclosed is a process for the manufacture of a Compound of formula (I) wherein Hal represents fluoro or chloro, and R 1  and R 2  represent, independently from one another, hydrogen or Hal; in which process a Compound of formula (II) is converted to a corresponding alkyl, fluoroalkyl or aryl sulfonic acid ester, which is then reacted with an alkali metal nitrite in the presence of a suitable crown ester in a polar non-nucleophilic solvent at a temperature of −10 to 50° C. to give the Compound of formula (I).

The present invention relates to a process for the manufacture of(2R,3R)-3-(halogenophenyl)-3,4-epoxy-2-butanol derivatives which areuseful in the synthesis of azole antifungal compounds like e.g.(1R,2R)-4-[2-[2-(2,4-Difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl]benzonitrileor, in particular,(1R,2R)-4-[2-[2-(2,5-Difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl]-benzonitrile(BAL 4815) and to a process for manufacturing such azole antifungalcompounds using the aforementioned process.

Processes for the preparation of(2R,3R)-3-(halogenophenyl)-3,4-epoxy-2-butanol derivatives are known inthe art. The known processes usually start from the rather costlyR-lactic acid or D-(−)-lactic acid. For example, US 2003/0236419 A1discloses a process for manufacturing(2R,3R)-3-(2′,4′-difluorophenyl)-3,4-epoxy-2-butanol wherein D-methyllactate is converted to (2R)-2′,4′-difluoro-2-hydroxy-propiophenone,which is then reacted with trimethyloxosulfonium bromide/sodium hydrideto give a 12:1-mixture of(2R,3R)-3-(2′,4′-difluorophenyl)-3,4-epoxy-2-butanol and thecorresponding (2R,3S)-compound. A similar reaction is described inWO99/45008 for manufacturing(2R,3R)-3-(2′,5′-difluorophenyl)-3,4-epoxy-2-butanol.

WO 9952840 A1, on the other side, discloses the use of the much lessexpensive S-lactic acid (L-(+)-lactic acid) instead of R-lactic acid asthe basic starting material for(2R,3R)-3-(2′,4′-dihalogenophenyl)-3,4-epoxy-2-butanol derivatives. Itis, however, necessary to change the configuration of carbon atom 2 ofthe butanol skeleton in course of said process in order to arrive at thedesired R-configuration at said carbon atom. This is achieved accordingto WO 9952840 A1 via the well-known Mitsunobu Reaction, wherein theintermediate (2S,3R)-3-2′,4′-dihalogenophenyl)-3,4-epoxy-2-butanolderivative is reacted with p-nitrobenzoic acid in the presence oftriphenylphosphine and diethylazodicarboxylate (DEAD) to give(2R,3R)-3-(2′,4′-dihalogenophenyl)-3,4-epoxy-2-butanol p-nitrobenzoicacid ester, which is then saponified to the corresponding butanolderivative.

Said Mitsunobu Reaction step however has several disadvantages, inparticular if is to be applied on a technical scale. It provides onlyunsatisfactory yields of the desired (2R,3R) derivative, produces anunacceptable quantity of waste, and said process step is only difficultup-scalable, if at all, because substantial problems with thepurification of the product arise at a larger scale.

in particular, If the classical Mitsunobu conditions, disclosed in WO9952840 A1 in connection with the manufacture of(2R,3R)-3-(2′,4′-difluorophenyl)-3,4-epoxy-2-butanol, is applied to therespective 2′,5′-difluoro analog, an unsatisfactory yield of only about50% can be obtained. Moreover, the enantiomeric excess observed is onlyabout 90%, hence no full conversion reversal is achieved.

It has now been found, however, that using instead a specificalternative of the Mitsunobo step in the manufacture of(2R,3R)-3-(halogenophenyl)-3,4-epoxy-2-butanol provides much betteryields, and has not the disadvantages associated with said reactionstep.

A first subject of the present invention is therefore a process for thepreparation of a compound of formula (I)

whereinHal represents fluoro or chloro, andR¹ and R² represent, independently from one another, hydrogen or haveone of the meanings of Hal;in which process a compound of formula (II)

is converted to a corresponding alkyl, fluoroalkyl or aryl sulfonic acidester, which is then reacted with an alkali metal nitrite in a polarnon-nucleophilic solvent at a temperature of minus 10° C. to 50° C. andin the presence of a suitable crown ester, to give the compound offormula (I).

Suitable alkyl or aryl sulfonic acid esters include for examplep-toluene sulfonic acid ester, methyl sulfonic acid ester and inparticular trifluoromethyl sulfonic acid ester. The conversion of thecompound of formula (II) to the corresponding alkyl or aryl sulfonicacid esters can be accomplished in a way known per se, e.g. by reactingthe compound of formula (II) with an alkyl or aryl sulfonic acid halide,e.g. the chloride, or preferably the anhydride in the presence of a baselike e.g. pyridine, preferably at temperatures between minus 10° C. and50° C., more preferably between minus 10° C. and 10° C., e.g. at 0° C.,in a non-polar solvent like e.g. methylene chloride. The ratio of alkylor aryl sulfonic acid derivative, e.g. the respective halide oranhydride, in particular the trifluoromethylsulfonic acid anhydride, andthe compound of formula (II) is preferably between 1:1 and 3:1, morepreferably between 1.5:1 and 2.5:1. The base, e.g. pyridine, is used inabout the same quantities as the alkyl or aryl sulfonic acid derivative.Suitable reaction times range from about 15 minutes to several hours,e.g. 10 hours, preferably from 1 to 3 hours.

After optional purification of the reaction product and/or removal ofthe solvent, the alkyl, fluoroalkyl or aryl sulfonic acid ester of thecompound of formula (II) is dissolved in a polar non-nucleophilicsolvent like, for example, dimethylsulfoxide (DMSO),N,N-dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),tetrahydrofurane (THF), dioxane or formamide, and is reacted with anexcess of an alkali metal nitrite, e.g. sodium, potassium or caesiumnitrite, in the presence of a suitable crown ether as catalyst.

Preferably a two- to tenfold excess of the alkali metal nitrite is used,more preferably a four- to sixfold excess. Suitable crown ethers can bereadily chosen by those skilled in the art, mainly depending on whatalkali metal nitrite is applied, and include 18-crown-6-ether,15-crown-5-ether, 12-crown-4 ether. 18-crown-6-ether is specificallypreferred, in particular when used with potassium nitrite. As mentioned,it is used in catalytical amounts, e.g. in an amount ranging from athousandth to a tenth part of the molar quantity of the alkali metalnitrite. The reaction is preferably carried out at about 10 to 30° C.,more preferably at about 15 to 25° C., e.g. at room temperature.

After completion of the reaction, the mixture is preferably treated withdiluted aqueous sodium hydroxide, preferably for a time period of aboutone hour. Then the compound is preferably extracted with an appropriatesolvent or solvent mixture. The solvents used include e.g. ethylacetate, linear or branched C₅₋₈ alkanes, methyl acetate, ethyl acetatewhich is especially preferred, propyl acetate, and symmetric orasymmetric dialkyl ethers, the alkyl groups of which comprise from 1 to5 carbon atoms. After extraction and appropriate washing (brine) thecompound (I) can be used as is, directly without further purificationrequired.

Particularly preferred embodiments of the process according to thepresent invention accordingly include a process as described abovewherein the compound of formula (II) is converted to thetrifluoromethylsulfonic acid ester and then further processed.Furthermore preferred is the process of the present invention, whereinthe alkali metal nitrite is sodium or, more preferably, potassiumnitrite, as well as the process of the invention, wherein the crownester is the 18-crown-6 ester when potassium nitrite is used and15-crown-5-ether when sodium nitrite is used. In a further preferredembodiment of the aforementioned process, dimethylsulfoxide (DMSO),N,N-dimethylformamide (DMF),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),Tetrahydrofurane (THF), dioxane or formamide, in particular DMF, areused as the polar non-nucleophilic solvent, or suitable mixtures of saidsolvents.

A further preferred embodiment is a process of the present invention formanufacturing compounds of formula (I), wherein Hal represents fluoro,and one of R¹ and R² represents hydrogen and the other fluoro, inparticular if R¹ represents fluoro and R² hydrogen. By the way ofexample, in case of manufacturing(2R,3R)-3-(2′,5′-difluorophenyl)-3,4-epoxy-2-butanol, yields of about80% and more can be achieved with the process of the present invention,with no other diastereoisomers being detected, whereas the standardMitsunobu reaction yields only about 50% as already mentioned above.

The compounds of formula (II) can, in general, be obtained according tothe following Reaction Scheme 1:

The compound of formula (VI) can, for example, be manufactured byreacting a compound of formula (V), wherein Hal represents fluoro, orchloro more preferably fluoro, and R¹ and R² represent, independentlyfrom one another, hydrogen or fluoro, or chloro, more preferably fluoro,and X is Iodo or preferably bromo, with magnesium in a suitable organicsolvent like THF and in a manner known per se to form the magnesiumbromide of the compound of formula (V); i.e. said compound wherein Xrepresents MgBr. This compound is then further reacted with the compounda formula (III), wherein PrG represents a hydroxyl-protecting group likee.g. benzyl, trityl, methoxymethyl, 1-ethoxy-ethoxyl,methoxyethoxymethyl, SiMe₃, SiEt₃ SiMe₂tBu, SiPh₂Me, COMe, COEt, COiPr,COBu, COsecBu, COtBu, or, in particular, 2-tetrahydropyranyl, R³represents methyl or ethyl, and R⁴ represents methyl, ethyl or methoxy(Weinreb amide), or R³ and R⁴ taken together with the nitrogen atom towhich they are bound represent a 4- to 6-membered heterocyclic grouphaving either no or one or two further heteroatoms selected fromnitrogen or oxygen; e.g. like e.g. a pyrrolidine, imidazolidine,pyrazolidine, piperazine or, in particular, morpholine residue. Apreferred compound of formula (III) is(2S)-1-Morpholin-4-yl-2-(tetrahydropyran-2-yloxy)-propan-1-one (whichcan be obtained, for example, as described in Chem. Pharm. Bull. 41,1035, 1993). The reaction is preferably performed at a temperaturebetween minus 10° C. and room temperature, i.e. 20° C. to 25° C. overabout 1 to 10 hours, preferably 3 to 8 hours. A preferred solvent forthis reaction is THF.

The compound of formula (VI) can, for example, be converted to acompound of formula (VII) by reacting compound of formula (VI) withmethyl triphenyl-phosphonium bromide and lithiumbis(trimethylsilyl)amide, preferably in amounts of 1 to 2 moleequivalent per mole of the compound of formula (VI), in a suitablesolvent like THF, a dialkyl ether, dioxane, DMF or DMSO. Suitablereaction temperatures range from about minus 70° C. to 50° C. Reactiontimes are generally between 1 to 24 hours, preferably between 1 and 15hours.

The compound of formula (VII-a) can be obtained by reaction of thecompound of formula (VII) with about 0.1 to 1 mole ofpyridinium-p-toluenesulfonate per mole of the compound of formula (VII)in an alcohol as solvent, preferably methanol, ethanol or propanol,during about 1 to 24 hours, preferably 1 to 10 hours, and at atemperature ranging from 0 to 60° C. preferably 30° C.

The compound of formula (II) is enantioselectively obtainable from acompound of formula (VII-a) via the well-known Sharpless Epoxidationroute, i.e. the reaction of the compound of formula (VII-a) with about 1to 5 mole of t-butyl hydroperoxide (TBHP) per mole of the compound offormula (VII-a) in the presence of about 0.1 to 1, preferably about 0.5,mole titanium(IV) isopropoxide (TIPO) per mole of the compound (VII-a)and 0.1 to 1, preferable 0.3, mole of a dialkyl L(+)-tartrate,preferably L(+)-diethyl tartrate. Preferred solvents for said reactioninclude chloroform and particularly methylene chloride, to whichmolecular sieve powder (about 3 to 4 angstroms) is added. Suitablereaction temperatures range from minus 30 to room temperature (20 to 25°C.), preferable from about minus 25 to about 10° C., suitable reactiontimes range between 5 and 20 hours, e.g. 8 to 15 hours.

In a further aspect the present invention relates also to a process forthe manufacture of a compound of formula (IV-a).

wherein PrG represents a hydroxyl-protecting group,in which process 1,4-difluorobenzene is reacted in the presence of abase with a compound of formula (III-a)

whereinPrG has the same meaning as in Formula (IV-a).R³ represents methyl or ethyl, andR⁴ represents methyl, ethyl or methoxy, orR³ and R⁴ taken together with the nitrogen atom to which they are boundrepresent a 4- to 6-membered heterocyclic group having either no or oneor two further heteroatoms selected from nitrogen or oxygen.

PrG, R³ and R⁴ have preferably the same meaning as indicated alreadyabove, most preferably PrG represents a tetrahydropyran-2yl residue andR³ and R⁴ taken together with the nitrogen atom to which they are boundrepresent a morpholin-4-yl group.

Suitable bases for use in said reaction include strong bases like amidbases, e.g. lithium hexamethyldisilazane (LiHMDS), sodiumhexamethyldisilazane (NaHMDS) or potassium hexamethyldisilazane (KHMDS),lithiumdiisopropylamine (LDA), butyllithium (BuLi), or sodiumtert-butylate (KOtBu) and the like and mixtures thereof, the mostpreferred base being LDA.

Suitable as solvents are, in general, aprotic, inert solvents like e.gTHF or dioxane.

The compound of formula (III) is preferably added at relatively lowtemperatures during said process, and the reaction temperature rangespreferably from minus 78° C. to 15° C. Particularly suitable reactiontemperatures are about 10° C.

The aforementioned process is particularity suitable for manufacturingthe (2S,3R)-3-2′,5′-difluoro)-3,4-epoxy-2-butanol of formula (II-baccording to the following Reaction Scheme 1-a) and it allows to startwith 1,4-difluorobenzene which must not be converted beforehand to1-bromo-2,5-difluorobenzene as would be the case when using the Grignardroute described above.

This reaction cannot be used with 1,3-difluorobenzene as the startingmaterial because with this compound alkylation almost quantitativelytakes place in the 2-position i.e. between the two fluoro substituents.

For synthesis of azole antifungal compounds like(1R,2R)-4-[2-[2-(2,4-difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl]-benzonitrileor, in particular,(1R,2R)-4-[2-[2-(2,5-difluoro-phenyl)-2-hydroxy-1-methyl-3-[1,2,4]triazol-1-yl-propyl]-thiazol-4-yl]-benzonitrilethe intermediates of formula (I) must be further processed.

In a special embodiment of the process according to the presentinvention the compound of formula (I) as obtained in the process ofclaim 1 is therefore reacted with 1,2,4-triazole in the presence of abase to give a compound of formula (VIII)

wherein Hal, R¹ and R² have the same meaning as in formula (I), and saidcompound is then converted to a compound of formula (IX):

wherein Hal, R¹ and R² have also the same meaning as in formula (I).

This reaction is described, for example, in WO99/45008. The compound offormula (I) is e.g. reacted with a two to fivefold excess of1,2,4-triazole in the presence of a base like sodium hydride in a drysuitable solvent like DMF or DMSO at a temperature between 50 and 100°C. for about 1 to 12 hours, preferably 2 to 5 hours. The obtainedcompound of formula (VIII) is optionally purified and is then reacted ina suitable solvent like e.g. methylene chloride with methylsulfoniumchloride in the presence of an organic base like pyridine ortrimethylamine for 0.5 to 5 hours at a temperature of minus 10 to 10°C., e.g. about 0° C. Then a base, like NaOH or NaOMe is added to performthe epoxy ring formation, and the epoxy product is preferably purified.

In a particularly preferred embodiment of the process of the presentinvention the compound of formula (IX) is further converted to acompound of formula (X)

wherein Hal, R¹ and R² have the same meaning as in formula (IX), andsaid compound of formula (X) is then reacted with dithiophosphoric acidO,O-diethyl ester or ammonium sulfide to give a compound of formula(XI):

wherein Hal, R¹ and R² have the same meaning as in formula (X), which isthen reacted with 2-bromo-4′-cyano-acetophenone to give a compound offormula (XII):

wherein Hal, R¹ and R² have the same meaning as in formula (XI).

Suitable parameters for the aforementioned reaction steps are in moredetail described, for example, in WO99/45008. The compound of theformula (X) is reacted with dithiophosphoric acid O,O-diethyl ester andwater or dithiophosphoric acid O,O-diethyl ester, water and isopropanol,e.g. at a temperature between 90° C. and 150° C. for 4 to 8 hr. to givethe compound of the formula (XI), followed by reacting said compoundwith the 2-bromo-4′-cyanoacetophenone at a temperature between roomtemperature and about 80° C. in acetonitrile, ethanol or methanol, e.g.for 2 to 24 hours to give the compound of the formula (XII). If desired,salt formation by known procedures may follow. Hydrates or solvates withpharmaceutically acceptable solvents such as ethanol can also beobtained, for example, during crystallization.

A preferred specific embodiment of the present invention is the use ofthe process according to the present invention in the manufacture of acompound of formula (XII-a)

or a pharmaceutically acceptable salt, hydrate of solvate thereof;

EXAMPLE 1(2S)-1-(2,5-Difluoro-phenyl)-2-(tetrahydro-pyran-2-yloxy)-propan-1-one

1,4-Difluorobenzene (1.8 g; 15.8 mmol) and(2S)-1-Morpholin-4-yl-2-(tetrahydro-pyran-2-yloxy)-propan-1-one (3 g;10.5 mmol) are dissolved in dry THF (15 ml). The mixture is cooled to 0°C. and then lithium diisopropylamine (7.9 ml of a 2M solution inTHF/Heptane; 15.8 mmol) is added dropwise over a period of 20 minutes.The mixture is stirred for another 2 hours at 0° C. The reaction is thenquenched with a saturated ammonium chloride solution. The reactionmixture is extracted with ethyl acetate. The organic phase is washedwith water and brine and then dried over magnesium sulfate. The solidsare filtered off and the solvent is removed under reduced pressure. Thecrude product is chromatographed over silicagel (eluent:Petrolether/Ethyl acetate 50:1 to 30:1). 1.31 g of yellow crystalline material(yield 44.8%) is obtained with a HPLC purity of 96.2%.

NMR: (CDCl₃; 400 MHz): 7.53-7.47 (m; 1H); 7.24-7.16 (m; 1H); 7.15-7.07(m; 1H); 5.10 (qd; J=7.2 Hz; 2.0 Hz; ½H); 4.85 (q; J=7.2 Hz; ½H); 4.74(m; ½H); 4.64 (m; ½H); 3.89 (m; ½H); 3.71 (m; ½H); 3.51 (m; ½H); 3.34(m; ½H); 1.90-1.48 (m; 6H); 1.47 (d; J=7.2 Hz; 1.5H); 1.42 (d; J=7.2 Hz;1.5H).

EXAMPLE 21(S)-[2-(2,5-Difluoro-phenyl)-1-methyl-allyloxy]-tetrahydro-pyran

Methyl triphenylphosphonium iodide (11.1 g; 27.7 mmol) was suspended indry THF (100 ml). The reaction mixture is cooled in an ice bath. Asodium bis(trimethylsilyl)amid solution (30 ml of a 1M solution in THF)is added at such a rate to keep the temperature below 20° C. Thereaction mixture was stirred for 3 hours at 15° C. then was cooled at−78° C. Then(2S)-1-(2,5-Difluoro-phenyl)-2-(tetrahydro-pyran-2-yloxy)-propan-1-one(5.0 g; 15.7 mmol in solution in THF (20 ml)) is added to the previousmixture at such a rate to keep the temperature below −70° C. The mixtureis stirred 5 minutes at this temperature then for 17 hours at 10° C.

Then ethyl acetate (5 ml) and hexanes (350 ml) was added. The suspensionwas stirred for 15 minutes (precipitation of triphenylphosphine-oxide).The solids were filtered off. The filter-cake was washed with hexane (60ml). The filtrate is washed twice with a 1:1 water methanol mixture (2times 100 ml) and with brine (100 ml). The organic phase is dried overmagnesium sulfate. The solids are filtered off and the solvent isremoved under reduced pressure. The crude product is chromatographedover silicagel (eluent:Petrol ether/Ethyl acetate 20:1 to 10:1). 3.45 gof a colorless oil (yield 69%) is obtained with a HPLC purity of 99.9%and ee is 99.2%.

NMR: (CDCl₃; 400 MHz): 7.02-6.94 (m; 3H); 5.58 (s; 1H); 5.23 (s; 1H);4.76 (m; 1H); 4.66 (q; J=7.2 Hz; 1H); 3.94 (m; 1H); 3.55 (m; 1H);1.90-1.48 (m; 6H); 1.27 (d; J=7.2 Hz; 3H).

EXAMPLE 3 2(S)-3-(2,5-Difluoro-phenyl)-but-3-en-2-ol

1(S)-[2-(2,5-Difluoro-phenyl)-1-methyl-allyloxy]-4-tetrahydro-pyran(5.79 g; 20.4 mmol)) was dissolved in methanol (40 ml). Pyridiniumtoluene sulfonate (2.61 g; 10.4 mmol) is added and the mixture isstirred at 35° C. for 12 hours. The solvent was removed under reducedpressure. The residue was taken up in ethyl acetate (40 ml) and thesolids are filtered off. The crude product is chromatographed oversilicagel (eluent:Petrol ether/Ethyl acetate 200:1 to 50:1). 3.45 g of ayellow oil (yield 81.4%) is obtained with a HPLC purity of 99.9%; ee:99.2%.

NMR: (DMSO D6; 400 MHz): 7.27-7.13 (m; 3H); 5.50 (sbr; 1H); 5.14 (sbr;1H); 5.12 (d; J=4.8 Hz; OH); 4.51 (m; 1H); 1.06 (d; J=6.8 Hz; 3H).

EXAMPLE 4 1(R)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol

L-(+)-Diethyl tartrate (7.9 g; 38.2 mmol) is dissolved in dry methylenechloride (250 ml) at −30° C. and molecular sieves 4A are added (8 g).Titanium tetraisopropoxide (TIPO) (10.8 g; 36.5 mmol) is added to themixture. The mixture is stirred 1 hour at −30° C. Then2(S)-3-(2,5-Difluoro-phenyl)-but-3-en-2-ol (7 g; 33.2 mmol) dissolved indry methylene chloride (50 ml) is added slowly. The mixture is stirredone hour −30° C. then Tert-butyl hydroperoxide (TBHP) (13.2 ml of a 5.5Msolution in decane; 73.1 mmol) is added dropwise at −25° C. The mixtureis stirred 12 hours at −25° C. The reaction mixture is warmed up to 10°C. and an aqueous solution of ferrous sulfate (18 g) and tartaric acid(18 g) in water (300 ml) is added. The mixture is stirred at 10° C. for30 minutes. The phases are separated and the aqueous phase is extracted3 times with methylene chloride (3 times 250 ml). To the combinedorganic phases a 1M aqueous sodium hydroxide solution (100 ml) is addedand the mixture is stirred for one hour. The phases are separated andthe aqueous phase is extracted twice with methylene chloride (2 times 50ml). The organic phase is dried over magnesium sulfate. The solids arefiltered off and the solvent is removed under reduced pressure. Thecrude product is chromatographed over silicagel (eluent:Petrolether/Ethyl acetate 20:1). 6.55 g of a light yellow oil (yield 82%) isobtained with a HPLC purity of 82%.

NMR: (CDCl₃; 400 MHz): 7.12-7.10 (m; 1H); 7.09-6.98 (m; 2H); 4.12(m(br); 1H); 3.28 (d; J=4.8 Hz; 1H); 2.91 (d; J=4.8 Hz; 1H); 2.28(d(br); OH); 1.23 (d; J=6.5 Hz; 3H).

EXAMPLE 5 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol

1(R)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (500 mg; 2.34 mmol;HPLC purity 93%) is dissolved in dry methylene chloride (25 ml). Drypyridine (0.38 ml; 4.67 mmol) is added and the reaction mixture iscooled to 0° C. Then trifluoromethanesulfonic anhydride (0.88 ml; 5.14mmol) is added dropwise. The reaction mixture is stirred at 0° C. for 15minutes. Then 5 drops of 5% aqueous sulfuric acid and water (5 ml) isadded and the phases are separated. The aqueous layer is extracted 3times with ethyl acetate (3 times 20 ml). The combined organic phasesare first washed with 2M aqueous hydrochloric acid solution (20 ml),with a saturated bicarbonate solution (20 ml) and finally with brine (20ml). The organic phase is dried over magnesium sulfate. The solids arefiltered off and the solvent is removed under reduced pressure.

The obtained crude oil (0.766 g) is used as is for the followingtransformation.

NMR: (CDCl₃; 400 MHz): 7.17-7.12 (m; 1H); 7.11-7.06 (m; 2H); 5.18 (q;J=6.6 Hz; 1H); 3.23 (d; J=4.5 Hz; 1H); 2.97 (d; J=4.5 Hz; 1H); 1.51 (d;J=6.6 Hz; 3H).

The previously prepared triflate (766 mg; 2.31 mmol) is dissolved in DMF(20 ml distilled prior to use). Potassium nitrite (981 mg; 11.5 mmol)and 18Crown6 (37 mg; 0.41 mmol) are added and the mixture is stirred at18° C. for half an hour. The reaction mixture is diluted with ethanol (5ml). Sodium hydroxide (138 mg; 3.46 mmol) and water (5 ml) is added. Themixture is stirred at 18° C. for one hour. The reaction mixture isextracted 3 times with ethyl acetate (3 times 20 ml). The combinedorganic phases are first washed with brine (10 ml). The organic phase isdried over magnesium sulfate. The solids are filtered off and thesolvent is removed under reduced pressure. The residue ischromatographed over silicagel (eluent:Petrolether/Ethyl acetate:20:1).305 mg of a light yellow oil (yield: 65%) is obtained.

NMR: (CDCl₃; 400 MHz): 7.16-7.12 (m; 1H); 7.05-6.97 (m; 2H); 4.17(m(br); 1H); 3.33 (d; J=4.8 Hz; 1H); 2.80 (d; J=4.8 Hz; 1H); 1.87(d(br); OH); 1.17 (d; J=6.5 Hz; 3H).

EXAMPLE 6(2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]-triazol-1-yl-butane-2,3-diol

1,2,4-Triazole (274 mg; 3.89 mmol) is dissolved in DMSO (3 ml). Sodiumhydride (124 mg; 60% suspension in paraffin; 3.24 mmol) is added and thereaction mixture is heated to 70° C. for one hour. The reaction mixtureis cooled to room temperature and1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (275 mg; 1.3 mmol)dissolved in DMSO (2 ml) is added slowly over a period of 10 minutes.The reaction mixture is then heated to 70° C. for three hours. Thesolvent is evaporated. The residue is taken-up in ethyl acetate (10 ml)and water (5 ml). The phases are separated. The aqueous layer isextracted 3 times with ethyl acetate (3 times 5 ml). The combinedorganic phases are washed twice with water (2 times 5 ml). The organicphase is dried over sodium sulfate. The solids are filtered off and thesolvent is removed under reduced pressure. The crude product isdissolved in ethyl acetate (16 ml). Oxalic acid (164 mg; 1.3 mmol) isadded and the solution is stirred for 30 minutes. The mixture is storedat 0° C. overnight. The crystalline(2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-dioloxalate salt is filtered off. The crystals are washed with hexanes anddried under vacuum. The desired compound is obtained as a white powder(337 mg); yield 66.7% with an optical purity higher than 95% (no otherisomer is visible in NMR).

NMR: (DMSO D6; 400 MHz): 8.32 (s; 1H), 7.61 (s; 1H); 7.13 (m; 1H); 7.07(m; 1H); 6.93 (m; 1H); 5.55 (s(br); 2H OH, NH); 4.70 (s; 2H); 4.22(m(br); 1H); 0.81 (d; J=6.5 Hz; 3H).

EXAMPLE 7(2(R),3(S))-1-[2-(2,5-Difluoro-phenyl)-3-methyl-oxiranylmethyl]-1H-[1,2,4]triazole

(2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]-triazol-1-yl-butane-2,3-diol(324 mg; 1.20 mmol) is dissolved in methylene chloride (13 ml).Triethylamine (0.59 ml; 4.2 mmol) is added to the reaction mixture. Thereaction mixture is cooled to 0° C. and methane sulfonyl chloride (0.21ml; 2.72 mmol) dissolved in methylene chloride (4 ml) is added. Thereaction mixture is stirred 4 hours at 0° C. Then a 6M aqueous sodiumhydroxide solution (0.98 ml) is added. The reaction mixture is stirredat room temperature overnight. The solvent is evaporated. The residue istaken-up in ethyl acetate (15 ml) and water (8 ml). The phases areseparated. The aqueous layer is extracted 3 times with ethyl acetate (3times 10 ml). The combined organic phases are washed twice with water (2times 5 ml). The organic phase is dried over sodium sulfate. The solidsare filtered off and the solvent is removed under reduced pressure. Thecrude compound is chromatographed (eluent:Ethyl acetate/Petrol ether1:2) and desired compound is obtained as white crystals (116 mg); yield38.5%.

HPLC purity: 99.5%

ee: 99.99%

NMR: (CDCl₃; 400 MHz): 7.98 (s; 1H); 7.73 (s; 1H); 7.00-6.88 (m; 2H);6.77 (m; 1H); 4.97 (d; J=14.5 Hz; 1H); 4.41 (d; J=14.5 Hz; 1H); 3.19 (q;J=5.6 Hz; 1H); 1.64 (d; J=5.6 Hz; 3H).

EXAMPLE 8 1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol

DEAD (870 mg; 2 mmol) and p-nitrobenzoic acid (337 mg; 2 mmol) weredissolved in dry THF (3 ml) and the solution was cooled to 0° C. Then1(R)-[2(S)-2,5-Difluoro-phenyl)-oxiranyl]-ethanol (100 mg; 0.5 mmol) andtriphenylphosphine (524 mg; 2 mmol) is dissolved in dry THF (10 ml) wereadded dropwise at such a rate to maintain the temperature below 10° C.The mixture was then allowed to react to completion at 20° C. for 20hours. Half of the solvent was removed under reduced pressure. Thereaction mixture is diluted with diethyl ether (80 ml) and washed withan aqueous saturated ammonium chloride solution. The organic phase isdried over magnesium sulfate. The solids are filtered off and thesolvent is removed under reduced pressure. The residue is dissolved inmethanol (25 ml) and treated with potassium carbonate (450 mg). Thereaction mixture is diluted with an aqueous saturated ammonium chloridesolution (30 ml). The reaction mixture is extracted with ethyl acetate(2 times 20 ml). The combined organic phases are washed with water (2times 30 ml) and with brine (2 times 30 ml). The organic phase is driedover magnesium sulfate. The solids are filtered off and the solvent isremoved under reduced pressure. The crude residue is purified bychromatography (Petrole ether/ethyl acetate 20:1). 53 mg (yield: 53%) ofdesired 1 (S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol was obtainedas a colorless oil. The HPLC purity is 76%.

A small portion is converted to the triazolo-diol derivative in order todetermine the enantiospecificity of the reaction.

EXAMPLE 9(2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]-triazol-1-yl-butane-2,3-diol

1,2,4-Triazole (7 mg; 0.1 mmol) is dissolved in DMF (0.5 ml). Sodiumhydride (4.4 mg; 60% suspension in paraffin; 0.1 mmol) is added and thereaction mixture is heated to 70° C. for one hour. The reaction mixtureis cooled to room temperature and1(S)-[2(S)-(2,5-Difluoro-phenyl)-oxiranyl]-ethanol (5 mg; 0.025 mmolfrom example 8) dissolved in DMF (0.5 ml) is added slowly. The reactionmixture is then heated to 70° C. for three hours. The solvent isevaporated. The residue is taken-up in ethyl acetate (5 ml) and water (3ml). The phases are separated. The aqueous layer is extracted 3 timeswith ethyl acetate (3 times 5 ml). The combined organic phases arewashed twice with water (2 times 5 ml). The organic phase is dried oversodium sulfate. The solids are filtered off and the solvent is removedunder reduced pressure. 5 mg of(2R,3R)-2-(2,5-Difluoro-phenyl)-1-[1,2,4]-triazol-1-yl-butane-2,3-diolare obtained as a light yellow oil.

This compound was analyzed by chiral HPLC. The diastereoisomeric excesswas determined to be 94%.

1. A process for the preparation of a compound of formula (I)

wherein Hal represents fluoro or chloro and R¹ and R² represent,independently from one another, hydrogen or one of the meanings of Hal;in which process a compound of formula (II)

is converted to a corresponding alkyl, fluoroalkyl or aryl sulfonic acidester, which is then reacted with an alkali metal nitrite in thepresence of a suitable crown ether in a polar non-nucleophilic solventat a temperature of −10 to 50° C. to give the compound of formula (I).2. A process according to claim 1 wherein said alkyl sulfonic acid esteris the trifluoromethylsulfonic acid ester.
 3. A process according toclaim 1, wherein the alkali metal nitrite is sodium or potassiumnitrite.
 4. A process according to claim 1, wherein, in the event saidnitrite is potassium nitrite, the crown ether is the 18-crown-6 ether,in the event said nitrite is sodium nitrite, said crown ether is15-crown-3-ether.
 5. A process according to claim 3, wherein the alkalimetal nitrite is potassium nitrite.
 6. A process according to claim 1,wherein a solvent selected from the group consisting ofdimethylsulfoxide, N,N-dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),tetrahydrofurane, dioxane, formamide and mixtures thereof is used as thepolar non-nucleophilic solvent.
 7. A process according to claim 1,wherein, in formula (I), Hal represents fluoro and one of R¹ and R²represents hydrogen and the other fluoro.
 8. A process according toclaim 7, wherein R¹ represents fluoro and R² represents hydrogen.
 9. Aprocess according to claim 8, wherein the compound of formula (II) isobtained by a process which includes the reaction of 1,4-difluorobenzenewith a compound of formula (III)

wherein PrG represents a hydroxyl-protecting group, R³ represents methylor ethyl, and R⁴ represents methyl, ethyl or methoxy, or R³ and R⁴ takentogether with the nitrogen atom to which they are bound represent a 4-to 6-membered heterocyclic group having from 0 to 2 additionalheteroatoms selected from nitrogen or oxygen; in the presence of a base,to yield a compound of formula (IV)

wherein PrG has the same meaning as in Formula (III).
 10. A processaccording to claim 1, wherein the compound of formula (II) is obtainedby a process which includes reacting a compound of formula (V)

wherein Hal represents fluoro or chloro, X represents iodo or bromo, andR¹ and R² represent, independently from one another, hydrogen, fluoro orchloro; with magnesium, and the obtained product is reacted with acompound of formula (III)

wherein PrG represents a hydroxyl-protecting group, R³ represents methylor ethyl, and R⁴ represents methyl, ethyl or methoxy, or R³ and R⁴ takentogether with the nitrogen atom to which they are bound represent a 4-to 6-membered heterocyclic group having from 0 to 2 additionalheteroatoms selected from nitrogen or oxygen; to yield a compound offormula (VI)

wherein PrG has the same meaning as in formula (III) and R¹ and R² havethe same meaning as in formula (V).
 11. A process according to claim 9,wherein R³ and R⁴ taken together with the nitrogen atom to which theyare bound represent a morpholin-4-yl residue.
 12. A process according toclaim 1 including the process step wherein the compound of formula (VI)

wherein Hal, R¹ and R² have one of the meanings defined in claim 1, andPrG represents a hydroxyl-protecting group, is converted to a compoundof formula (VII)

wherein Hal, R¹ and R² have the same meaning as in formula (VI) and R⁶represents PrG or hydrogen.
 13. A process according to claim 12, whereinthe compound of formula (VII) is deprotected when R⁶ represents ahydroxyl-protecting group PrG, and/or converted to the compound offormula (II) via Sharpless Epoxidation:

wherein Hal, R¹ and R² have the same meaning as in formula (VI).
 14. Aprocess according to additionally including the further step of reactingsaid compound of formula (I) 1,2,4-Triazole in the presence of a base togive a compound of formula (VIII)

wherein Hal, R¹ and R² have the same meaning as in formula (I), whichcompound is then converted to a compound of formula (IX):

wherein Hal, R¹ and R² have the same meaning as in formula (I).
 15. Aprocess according to claim 14 further including the steps of convertingthe compound of formula (IX) to a compound of formula (X)

wherein Hal, R¹ and R² have the same meaning as in formula (IX),reacting said compound of formula (X) with dithiophosphoric acidO,O-diethyl ester or ammonium sulfide to give a compound of formula(XI):

wherein Hal, R¹ and R² have the same meaning as in formula (X), andfurther reacting said compound of formula (XI) with2-bromo-4′-cyano-acetophenone to give a compound of formula (XII):

wherein Hal, R¹ and R² have the same meaning as in formula (XI).
 16. Aprocess according to claim 15, wherein Hal, R¹ and R² are fluoro, fluoroand hydrogen, respectfully and said compound has the formula (XII-a)


17. (canceled)
 18. A process for the manufacture of a compound offormula (IV-a)

wherein PrG represents a hydroxyl-protecting group, in which process1,4-difluorobenzene is reacted in the presence of a base with a compoundof formula (III-a)

wherein PrG has the same meaning as in Formula (IV-a). R³ representsmethyl or ethyl, and R⁴ represents methyl, ethyl or methoxy, or R³ andR⁴ taken together with the nitrogen atom to which they are boundrepresent a 4- to 6-membered heterocyclic group having from 0 to 2additional heteroatoms selected from nitrogen or oxygen.
 19. A processaccording to claim 17, wherein R³ and R⁴ taken together with thenitrogen atom to which they are bound represent a morpholin-4-ylresidue.
 20. A process according to claim 17, wherein PrG represents a2-tetrahydropyranyl residue.
 21. A process according to claim 10,wherein R³ and R⁴ taken together with the nitrogen atom to which theyare bound represent a morpholin-4-yl residue.